Silibinin Retards Colitis-associated Carcinogenesis by Repression of Cdc25C in Mouse Model

Abstract

Purpose: Silibinin possesses the efficacy of anticancer and anti-inflammation. We aimed to test whether silibinin could prevent colitis-associated carcinogenesis in mouse model.

Experimental design: Azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to induce colitis-associated tumorigenesis in C57BL mice. Six-to-eight-week-old male mice were gavaged with 350 or 750 mg/kg of silibinin for 10 weeks right after DSS administration. The mice were then sacrificed, and colon tissues were measured for tumor multiplicity and size. Molecular changes about proliferation, apoptosis and inflammation were tested.

Results: Silibinin feeding showed a dose-dependent inhibition on the size of tumor induced by AOM/DSS in mice. In addition, silibinin inhibited cell proliferation evidenced by a decrease (P < 0.05) in Ki-67 and proliferating cell nuclear antigen (PCNA). However, silibinin did not show any significant effect on inflammation, apoptosis, and the mRNA expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF). The experiments in vitro showed that silibinin induced cell cycle arrest at G2/M phase in CT-26 cells, a mouse colonic cancer cell line. Furthermore, silibinin reduced the expression of Cdc25C and blocked the dephosphorylation of CDK1 at multiple sites both in vitro and in vivo.

Conclusions: Silibinin targets Cdc25C/CDK1 pathway and mitigates colitis-associated tumorigenesis in mice. Thus, our findings indicate the chemopreventive potential of silibinin for inflammation-associated colon cancer.

Keywords: Cdc25c; animal model; cell cycle arrest; colitis-associated carcinogenesis; silibinin.